BDNF prevents amyloid-β-induced exacerbation of mGluR5-driven Ca2+ transients in astrocytes through TrkB-Tc activation.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that, through the activation of its full length receptor, TrkB-FL, plays a pivotal role in neuroprotection, namely against neuronal toxicity mediated by amyloid-β peptide (Aβ). In astrocytes, the increase of calcium (Ca2+) signaling due the increase of metabotropic glutamate receptor type 5 (mGluR5) levels, induced by Aβ, has been considered deleterious for astrocytic function. In adition BDNF also increases intracellular calcium concentration ([Ca²⁺]ᵢ), in astrocytes, via activation of the truncated TrkB receptor isoform, TrkB-Tc. While the role of BDNF, in neurons, is well established, in terms of neuroprotection, its role in astrocytes, particularly in Aβ-induced toxicity conditions, remains less clear. Thus, this study aimed to evaluate the interplay between BDNF and Aβ in the modulation of [Ca2+]i signaling in primary cultures of cortical astrocytes. Ca2+ transients were induced by the activation of mGluR5 through the application of its agonist DHPG. In astrocytes pre-exposed to Aβ25-35 (10 µM, for 48-72 h), the Ca2+ transient amplitude was significantly increased compared to the control. A similar increase was observed in astrocytes incubated for 48 h with BDNF (20 ng/mL), or when astrocytes were simultaneously exposed to BDNF and Aβ. The effect of BDNF was mediated by TrkB-Tc since it was prevented by a cocktail of the three siRNAs against TrkB-Tc expression. mGluR5 levels were significantly increased in astrocytes pre-exposed to Aβ, while exposure to BDNF did not affect mGluR5 levels. Importantly, while the presence of Aβ did affect TrkB-Tc receptor levels in astrocytes, the presence of BDNF prevented the increase in mGluR5 levels caused by Aβ thus precluding a further exacerbation of Ca2+ transients caused by Aβ.